Background: Mucosal addressin cell-adhesion molecule (MAdCAM)-1, which is overexpressed on gut endothelium in active Crohn's disease (CD), promotes intestinal recruitment of integrin α4β7+ T cells that sustain chronic inflammation. As tumor necrosis factor alpha (TNF)-α, a cytokine centrally involved in CD, modulates gut endothelial adhesion molecules, we here explored the in vivo and ex vivo effects of TNF-α blockade on MAdCAM-1 expression in CD.
Methods: MAdCAM-1 was determined by immunoblotting in colonic biopsies collected before and 10 weeks after either infliximab or adalimumab treatment in CD patients, and in CD biopsies incubated with either infliximab or adalimumab or control IgG1. Integrin β7+ circulating T cells were analyzed by flow cytometry.
Results: MAdCAM-1 significantly decreased after either infliximab or adalimumab treatment in responder but not in nonresponder patients. In parallel, an increase of circulating β7+ T cells was found in responder patients only. A marked downregulation of MAdCAM-1 was observed in CD biopsies cultured with either infliximab or adalimumab in comparison to IgG1-treated biopsies.
Conclusions: Our findings showing that MAdCAM-1 is downregulated by TNF-α blockade point to a novel mechanism of action of anti-TNF-α antibodies in CD.
Article first published online 16 January 2013
*Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK
†First Department of Medicine, S. Matteo Hospital, Centro per lo Studio e la Cura delle Malattie Infiammatorie Croniche Intestinali, University of Pavia, Pavia, Italy
‡Division of Gastroenterology, IRCCS Istituto Clinico Humanitas, Milan, Italy.
Reprints: Professor Thomas T. MacDonald, Blizard Institute, Barts and the London School of Medicine and Dentistry, E1 2AT London, UK (e-mail: firstname.lastname@example.org).
P.B. and A.D.S. contributed equally to this work.
Received April 06, 2012
Accepted May 16, 2012